The Food and Drug Administration has learned of “hundreds of complaints” about the anti-allergy EpiPen device has misfired “during life-threatening emergencies.” In some cases involving misfiring, people later died. EpiPens are used to deliver a dose of the natural human hormone epinephrine to people who are suffering a potentially fatal allergic reaction known as anaphylaxis.

The FDA sent a warning letter to the division of drug giant Pfizer, which makes EpiPens for another pharmaceutical giant, Mylan, which is the leading seller of EpiPen auto-injectors.

The FDA letter cites multiple “significant” regulatory violations related to the manufacturing of EpiPen were discovered during inspections at a facility operated in Missouri by Meridian Medical Technologies, owned by Pfizer.

The facility is the same facility that had produced EpiPen lots that were subject to a recall in March 2017 after two reports of the auto-injector devices misfiring. At the end of that recall, which is mentioned in the FDA letter, there were no public reports of deaths associated with EpiPens.

In its letter dated Tuesday, September 5, 2017 to Meridian, the FDA wrote: “Your own data show that you received hundreds of complaints that your EpiPen products failed to operate during life-threatening emergencies, including some situations in which patients subsequently died.”

The FDA letter ordered Pfizer’s unit to correct the violations promptly. The agency’s letter also says failure to do so may result in legal action including seizure and injunction. The letter also warned the company to contact CDER’s (Center for Drug Evaluation and Research) Drug Shortages Staff immediately in case the company is considering an action that is likely to lead to disruption in the supply of products manufactured at the Meridian Medical Technologies facility.

Mylan came under criticism and public outrage in 2016 for continually raising the price of EpiPens starting in 2009. In 2007, the wholesale price of two EpiPens was about $100; the price was about the same in 2009; but by July 2013, the price was about $265. The 400+ percent increase in the prices of EpiPens occurred as Mylan launched a marketing campaign to increase awareness of the dangers of anaphylaxis for people with severe allergies, such as bee stings and peanut allergies. Mylan also successfully lobbied the FDA to broaden the label to include risk of anaphylaxis, while successfully lobbying Congress to generate legislation that would make EpiPens available in schools and in public places, similar to the way AEDs are now available in schools, restaurants and other public places. Mylan also hired the same people that Medtronic had worked with on defibrillator awareness.

In May 2015, the price of an EpiPen was around $461; and in May 2016, the price rose again to around $609,

The last price increase sparked widespread public outrage in the late summer as parents prepared to send their children back to school and went to pharmacies to get new EpiPens. Some consumers responded to the high price by buying EpiPens online from pharmacies outside the US,forgoing new EpiPens and relying on their expired EpiPens, which are known to be less effective.

In October 2016 the CEO of Mylan, Heather Bresch, a resident of Sewickley Heights, Pennsylvania, testified to Congress that Pfizer/King charged Mylan about $34.50 for one EpiPen. The devices deliver about $1 worth of drug. In September 2016, a Silicon Valley engineering consultancy performed a teardown analysis of the EpiPen and estimated the manufacturing and packaging costs at about $10 for a two-pack.

Heather Bresch is the daughter of the United States Senator from West Virginia Joseph Manchin III (D).

August 24, 2016 — Members of Congress are in an unusual position as they demand an explanation for Mylan NV’s 400 percent price hike for the EpiPen and focus attention squarely on its CEO: Heather Bresch. Bloomberg’s Toluse Olorunnipa reports on “Bloomberg Markets.”

Founder and former CEO of Turing Pharmaceuticals, Martin Shkreli, joins CBSN with to discuss why he believes the price hike of EpiPen is justified and why he raised the price of Daraprim by 5000%. Shkreli says the price of an EpiPen is a bargain compared to a $20,000 trip to the Emergency Room.

In December 2015, Martin Shkreli was arrested by the FBI after being indicted on federal charges of securities fraud. Shkreli subsequently resigned as CEO of Turing Pharmaceuticals and was replaced by the company’s board chairman, Ron Tilles. Shkreli was convicted of two counts of securities fraud and one count of conspiring to commit securities fraud in August 2017. Shkreli has not yet been sentenced.

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The U.S. Food and Drug Administration (FDA) inspected your manufacturing facility, Meridian Medical Technologies, Inc. (MMT) at 2555 Hermelin Drive, Brentwood, Missouri, from February 20 to March 24, 2017. The products you manufacture at this facility are combination products under section 503(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 353(g) as your products include drug and device constituent parts.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) requirements for combination products. See 21 CFR part 4, 21 CFR parts 210 and 211 (drug CGMP), and 21 CFR part 820 (Quality System or QS Regulation).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to drug CGMP requirements, 21 CFR parts 210 and 211, your combination products are adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351 (a)(2)(B).

In addition, your combination products are adulterated within the meaning of section 501 (h) of the FD&C Act, 21 U.S.C. 351(h), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with applicable CGMP provisions of the Quality System regulation (21 CFR part 820).

We reviewed your April 14, 2017, response in detail, and acknowledge receipt of your subsequent correspondence.

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21CFR211.192).1

Among other things, you manufacture two epinephrine auto-injectors at your facility, EpiPen and EpiPen Jr., (collectively, EpiPen products). These products are intended to deliver a lifesaving drug (epinephrine) during emergency treatment of serious allergic reactions, including anaphylaxis. If your auto-injectors do not operate as expected and deliver the intended amount of epinephrine drug when deployed in emergencies, patients can die or suffer serious illness. You failed to thoroughly investigate multiple serious component and product failures for your EpiPen products, including failures associated with patient deaths and severe illness. You also failed to expand the scope of your investigations into these serious and life-threatening failures or take appropriate corrective actions, until FDA’s inspection.

For example, on February 1, 2016, you identified a failing unit sampled from a single incoming lot of an auto-injector component, (b)(4) lot (b)(4). This component serves a critical role in the operation of your EpiPen products: it ensures that the auto-injector properly fires and delivers the intended dose of epinephrine. When you discovered a unit that failed to fire on receipt testing, you rejected the lot and one other associated lot of the same component, (b)(4). You did not examine any units from the associated lot to determine whether additional units were affected by the same or similar manufacturing defects. You instructed your supplier to undertake a full investigation and corrective actions regarding the firing defect, but continued to manufacture finished products using other lots of the same component while the supplier’s investigation remained open until October 2016. You did so without expanding your investigation, reviewing your incoming testing procedures to determine their adequacy or representativeness, or, at the time, linking the known component failure with numerous complaints you received regarding “failure to activate,” “difficult to activate,” or other product activation failures.

In fact, your own data show that you received hundreds of complaints that your EpiPen products failed to operate during life-threatening emergencies, including some situations in which patients subsequently died. Many of the complaints related to product activation failures, including failures to activate when the user followed the operating instructions, as well as failures for products that spontaneously dispensed epinephrine drug prior to use so that the drug was no longer available when the user attempted to activate the product. You did not thoroughly investigate these complaints. Moreover, we note that your follow up did not include removing potentially defective products from the marketplace, even though you had identified a defect in one of the critical components used to manufacture these products and even though you ultimately confirmed the same or similar component defect as the root cause for multiple complaints.

For example, on April 28, 2016, you received a customer complaint for an EpiPen that failed to activate (product lot number 5FA665). You opened an investigation on May 9, 2016, PR ID 22268, and confirmed that the product failed to activate. During your investigation, you disassembled the EpiPen for this complaint sample and determined the root cause was a deformed (b)(4) in the (b)(4) component of the auto-injector. This was the same type of manufacturing defect in the (b)(4) component that you confirmed in February 2016. Nonetheless, on June 3, 2016, you concluded that the defect was infrequent, even though you had not examined all of your reserve samples to determine the extent of the defect within the same lot of finished products, nor did you expand your investigation to other lots. You did not determine whether the defective component identified in this complaint sample might have been linked to the lots of components you rejected in February 2016, even though your component supplier was still investigating the matter and you had released multiple lots of finished product to the market that had been manufactured using the same potentially defective component. You closed your investigation and determined that “no market action would be taken.”

Between 2014 and 2017, your records show that you received 171 complaint samples for products that failed to activate when the patient followed the proper sequence. You disassembled only (b)(4) of the 171 samples you received as part of your investigations into these complaints. During our inspection, your site quality lead told our investigators that disassembly is necessary to detect (b)(4) defects, but that MMT’ s policy was not to disassemble the product unless “approved by management.” You offered no further explanation for failing to disassemble the vast majority of complaint samples you received over nearly three years, even though you concurred that disassembly would have been necessary to determine if a defective (b)(4) was present.

Finally, during our inspection, our investigators reviewed your investigations into these product failure complaints, and at our urging, you reopened the EpiPen lot 5F A665 investigation that you had closed in June 2016. You subsequently recalled that specific lot of auto-injectors after you determined that your component manufacturer had produced deformed (b)(4) affecting (b)(4). You used these (b)(4) lots in (b)(4) lots of EpiPen products, including EpiPen lot 5FA665. You distributed 13 of these (b)(4) EpiPen product lots to the United States market. While you eventually expanded the scope of the investigation into affected product lots and recalled all 13 lots distributed to the United States containing potentially deformed (b)(4), you did so only after our inspection closed and after multiple discussions with FDA.

In your response, you provided an analysis of defective (b)(4) and stated that you collaborated with your supplier to address the root cause of the defect. Your response is inadequate. You did not explain why your own investigations failed to identify the scope and frequency of the (b)(4) component defect, or why you had previously concluded that this component defect occurred too infrequently to warrant a market action. You also failed to review all of your investigations to determine whether you had assessed all lots of components and finished products potentially affected by this manufacturing defect. Finally, you did not determine a root cause for any failure-to-activate complaint samples that you determined had functioning (b)(4) and were thus not attributable to the same (b)(4) defect.

In response to this letter, provide:
• a comprehensive review of all your manufacturing investigations, including an evaluation of any other failures or discrepancies of a batch or any of its components that could potentially affect other products, whether or not they have been distributed or recalled; and
• your plans for addressing the patient safety and product quality risks for product still in distribution.

2. Your firm failed to establish and follow adequate written procedures describing the handling of all written and oral complaints regarding a drug product (21 CFR 211.198(a)).2

Complaint Classifications

Your procedures for handling complaints are inadequate. Your complaint classification scheme, listed in your standard operating procedure GPB-QS 1073 Prioritization of Pfizer Product Quality Complaints, describes three classifications – expedite, high, and normal – for customer complaints. This complaint scheme is deficient because it does not prioritize complaints based on risk to patients, which your site quality leader acknowledged during the inspection.

For example, you classify complaints for products that fail to activate when the patient has followed the proper sequence (subclass Proper Sequence Followed But Injection/Activation Failed) as “expedite.” However, you classify complaints for products that dispense the drug spontaneously (subclass Spontaneous Activation) prior to patient use as “normal,” your lowestpriority classification. Both problems result in the patient not receiving the needed drug in a lifethreatening situation.

In your response you stated that you would evaluate all complaint classifications and update your procedures. Your response is inadequate because you did not provide a sufficient rationale for how you determined which types of complaints fell into which categories. You did not discuss your plans for re-reviewing complaints previously categorized under this inadequate three-tiered scheme. Although you stated you would perform a risk assessment based on “medical” and “clinical” issues, you have not provided the results of this assessment, nor have you provided an updated risk classification scheme based on patient risk.

In response to this letter, provide your revised complaint classification scheme that prioritizes complaints commensurate with potential harm to patients, and your updated standard operating procedure for complaint classification and handling. Also provide your interim plan for addressing complaints you received before implementing your revised classification scheme and procedure to ensure that you have reviewed and handled complaints commensurate with the potential risks to patients.

Trend Analysis

As part of your complaint handling procedure you define a trend as “(b)(4) complaints of a similar nature on the same lot.” You have no scientific or statistical basis for defining a trend as (b)(4) similar complaints, and you stated to our investigators that you had no rationale for using this value.

In your response, you stated you would now use statistical analysis to determine if there was a potential trend for complaints of a similar nature within each lot. Your response is inadequate because you have only addressed intra-batch trending but have not indicated how you will compare different lots with one another. This trend analysis is critical in assessing the variability of quality attributes among different lots, understanding the sources of and addressing process variation, and indicating opportunities for process performance and product quality improvements.

In response to this letter, provide your procedure that includes a statistical trend analysis with both intra- and inter-batch bases for complaints received. Also provide a detailed analysis of complaint trends across all lots distributed within the last two years.

QS Regulation Violations

1. Failure to adequately analyze processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems. Appropriate statistical methodology shall be employed where necessary to detect recurring quality problems, as required by 21 CFR 820.100(a)(1).3 For example:

Causes of Nonconformities

Your firm does not distinguish between the different failure modes of rejected components/units that are collected in reject bins on the EpiPen manufacturing assembly line. For example, the Packaging and Inspection Master Specification for EpiPen ‘s Automated Assembly, Labeling, and Packaging instructs that (b)(4) which leads to commingling of different types of rejected components. Your firm does not assess the types or causes of rejects, and instead only records the total number of rejects. Therefore, your firm does not adequately analyze processes to identify existing and potential causes of nonconformities related to product or other quality problems.

We reviewed your firm’s response and conclude that it is not adequate. Your firm plans to develop a procedure to assess performance variability and to require routine (b)(4) trending of reject levels at (b)(4) which will determine action limits based upon process capability. Your firm’s response is not adequate because you have not provided this updated procedure with the aforementioned action limits, shown how you plan to use process capability in your analysis of processes, or indicated how this data will feed into your firm’s corrective and preventive action system.

Process Capability Analysis

Your firm does not use appropriate statistical methodology for process capability in order to analyze the quality of production machinery output at critical process steps and to detect recurring quality problems. Your firm’s Process Capability Report for EpiPen products states that you performed capability analysis on (b)(4) test results to determine process capability of the manufacturing operations involved in production. However, various specifications were only analyzed at the finished product attribute-level. Since capability is not determined at the (b)(4), and since the capability calculations were performed using final batch data collected after some defective units were removed, this analysis does not adequately demonstrate the ability to detect recurring quality problems.

We reviewed your firm ‘s response and conclude that it is not adequate. Your firm stated that it will incorporate routine machine capability studies and periodic reviews into ongoing trend analysis. However, you have not provided information regarding how you intend to monitor these studies, how the information will be used, and how it will feed into your corrective and preventative action system to detect and prevent recurring quality problems. Further, your response does not address the need to assess whether this capability analysis reveals other potential problems with the product, and the need to review the capability of other processes.

Statistical Methodology and CAPA

Your firm does not employ appropriate statistical methodology for analyzing complaint trends to identify recurring quality problems and/or existing and potential causes of nonconforming product. Product Complaint Handling SOP-QLC-QLE-00702 specifies how many complaints constitute a trend, and it requires trends to be investigated to identify the need for a corrective and preventive action (CAPA) plan. However, you have not used statistical analysis to justify your definition of a trend. Consequently, we note that CAP As were not adequately implemented to address several recurring issues seen in complaints and quality reports (QARs).

We reviewed your firm’s response and conclude that it is not adequate. Your response describes statistically based alert limits for similar complaints within the same lot, however it does not discuss alert limits for recurring quality problems that are not associated with a specific lot. Additionally, you do not discuss how complaint trends will be addressed by your firm’s CAPA system and trigger the requirements for implementing corrective and preventive actions.

2. Failure to adequately establish and maintain procedures for verifying the device design, as required by 21 CFR 820.30(f). Design verification shall confirm that the design output meets the design input requirements. The results of the design verification, including identification of the design, method(s), the date, and the individual(s) performing the verification, shall be documented in the DHF.

Your firm did not have adequate analysis to show that design verification ensured that the outputs for the EpiPen products conform to the defined inputs for the products. The occurrence of multiple serious component and product failures for your EpiPen products indicates a need to review the adequacy of your outputs to ensure conformance with the defined inputs. For example, your firm claims conformance to the ANSI/ASQ Z1.4 -2003 (R2013) standard in your design verification testing, and you have identified requirements and sample sizes for the design verification testing based on Acceptable Quality Levels (AQLs) from this standard. However, using the standard’s AQLs for design verification does not confirm that design outputs meet design inputs.

The ANSI/ ASQ Zl.4-2003 (R2013) standard states, in section 4.3, that “the AQL alone does not describe the protection to the consumer for individual lots or batches, but more directly relates to what is expected from a series of lots or batches provided the provisions of this standard are satisfied.” While ANSI/ASQ Z1.4 sampling plan ensures that lots having a quality level equal to the AQL are consistently accepted, it does not ensure that lots accepted will consistently achieve this quality level. In other words, your selection of sampling plans based on your specified AQL means that you would accept the design if it had a defect level equal to the AQL. However, it would not necessarily ensure that the design would be rejected if it had a defect level exceeding the AQL, i.e. a worse defect level. Therefore, your firm’s particular use of the ANSI/ASQ Z1.4 standard does not confirm that the design meets your particular quality requirements. Thus, you have not demonstrated that you adequately establish and maintain procedures for verifying your device design.

We reviewed your firm’s response and conclude that it is not adequate. In your firm’s response, you state that AQL is used to define sample sizes for testing, that no critical defects are allowed, and that you will (b)(4). However, this does not address the use of the ANSI/ASQ Z1.4 -2003 (R2013)’s AQLs for design verification, and as such, your design verification does not necessarily confirm that design outputs meet design inputs. Therefore, in response to this letter, provide information that demonstrates your sampling plans are written and based on valid statistical methods. In addition, please clarify how you determined the unacceptable quality level in design verification.

The occurrence of multiple serious component and product failures for your EpiPen products indicates issues with the ability of your product to conform to the defined user needs and intended uses. Your firm’s SOP for design verification and validation, Design Verification and Validation for New Products, Major Changes to Existing Products and Changes Affecting Product/User Interaction SOP-DVL-PRT-00004, describes the process for execution of design validation. However, your firm has not completed any validation testing of the design of EpiPen products in order to ensure that the products conform to the defined intended uses. Your firm’s representatives confirmed this, during the February-March 2017 inspection, when they stated that no design validation testing has been conducted for the EpiPen products.

We reviewed your firm’s response and conclude that it is not adequate. Your firm has not demonstrated that you have performed design validation. Therefore, in response to this letter, provide design validation of the finished combination product that ensures that the products conform to defined user needs and intended uses, and include risk analysis, where appropriate. Your firm’s analysis of design validation must address the finished combination product.

Risk Analysis

Your firm did not include risk analysis related to the design validation, where appropriate. Your firm’s SOP for design verification and validation for new products, Design Verification and Validation for New Products, Major Changes to Existing Products and Changes Affecting Product/ User Interaction SOP-DVL-PRT-00004, states that product risk assessment is an input that is required to start design validation. Although you informed investigators that you have a risk assessment document, you stated that you have not reviewed or updated the risk analysis since 2009. Therefore, you have not provided adequate risk analysis in your design validation to ensure that the products conform to their defined intended uses.

The adequacy of your firm’s response cannot be determined at this time. Although your firm’s response has discussed an updated risk assessment, your firm has not provided this document or the procedures that guide routine review of the document. Without evidence that risk analysis has been adequately performed, we are unable to assess whether design validation has been properly completed.

Quality Agreements

You and your customer, Mylan Specialty L.P., have a quality agreement regarding the manufacture of EpiPen products. You are responsible for the quality of combination products you produce as a contract facility, regardless of agreements in place with Mylan Specialty L.P. or with any of your suppliers. You are required to ensure that your combination products are compliant with the CGMP requirements applicable to each manufacturing process that occurs at your facility. See, generally, 21 CFR parts 4, 210, 211, and 820. See also FDA’s guidance document, Contract Manufacturing Arrangements for Drugs: Quality Agreements, at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm353925.pdf.

Repeat violations at facility

In a previous inspection of your facility from October 12 to November 25, 2014, FDA cited similar CGMP violations. You proposed specific remediation for these violations in your December 17, 2015, response. These repeated failures demonstrate that your facility’s oversight and control over the manufacture of these products is inadequate.

Conclusion

Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations in all your facilities.

If you are considering an action that is likely to lead to a disruption in the supply of products manufactured at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at [email protected], so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your manufacture under 21 U.S.C. 356C(b) and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

Until these violations are corrected, we may withhold approval of applications listing your facility. We may re-inspect to verify that you have completed your corrective actions.

We request that you contact Nabeel Babaa, by e-mail to [email protected], within five days of receipt of this letter to schedule a regulatory meeting.

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

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